1. Field of the Invention
The present invention relates to a novel method for preparing an imatinib base, and more particularly to a method of preparing an imatinib base using a novel thioester compound as a reaction intermediate.
2. Description of the Prior Art
Imatinib mesylate (chemical name: 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-ylamino]phenyl]benzamide mesylate) is an antitumor agent which is well known as the brand name Glivec of Novartis.
[Formula 1]

With respect to methods for preparing the compound of formula (1), which is an imatinib base, various technologies have been developed, and specific preparation methods are as follows.
Korean Patent Laid-Open Publication No. 10-1993-0005628 discloses the preparation of imatinib and the use thereof as an antitumor agent for the first time. The preparation method disclosed therein is as shown in the following reaction scheme (1).

In the method shown in reaction scheme (1), a palladium catalyst is used as a reducing agent for hydrogenation in the preparation of a compound of formula (3). The process for preparing the compound of formula (3) needs to be improved, because the process yield is as low as 40-50% and the palladium catalyst is expensive.
Then, a coupling reaction between N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyridinamine represented by formula (3) and 4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride represented by formula (7) is carried out to prepare a compound of formula (1).
The coupling reaction is carried out in the presence of an excess amount of pyridine, and the ratio of the pyridine to N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine represented by formula (3) is about 138 equivalents which is equivalent to about 40 parts V/W. Then, the obtained product is purified by chromatography, but the pyridine is toxic and is not easy to remove, and the chromatography process is expensive and time-consuming, and thus is not preferred in an industrial scale process.
In a similar method, Korean Patent Laid-Open Publication No. 10-1993-0005628 discloses the use of a similar pyridine/starting amine ratio (about 140 equivalents which is equivalent to about 41 parts V/W).
In Korean Patent Laid-Open Publication No. 10-2005-018358 which discloses another similar synthetic approach, in order to prepare a compound of formula (3) from a compound of formula (8), hydrogenation with a palladium catalyst was not carried out, a chemical reduction process was carried out using stannous chloride, and the yield was also increased to 65-75%. In addition, the coupling reaction between the compound of formula (3) and the compound of formula (7) was carried out using an inactive organic solvent in place of pyridine, thus preparing the compound of formula (1). However, stannous chloride used as the reducing agent in the preparation of the compound of formula (3) is expensive. Moreover, it is described that the inactive solvent is used in place of expensive pyridine in the preparation of the compound of formula (1), but the yield and purity of the compound of formula (1) are not disclosed.
As another similar method, an improved preparation method is disclosed in Korean Patent Laid-Open Publication No. 10-2009-0061068 and is as shown in the following reaction scheme (2).

In the method shown in reaction scheme (2), a carboxylic acid of formula (2) is activated using a halogenating agent such as thionyl chloride, after which the compound of formula (7) is produced as an intermediate, and then subjected to a coupling reaction with the compound of formula (3), thus preparing the compound of formula (1). This reaction is also carried out using a pyridine solvent in an amount of about 2-10 volumes (7-35 equivalents) per gram of the compound of formula (3), and thus the resulting product contains toxic pyridine. In addition, thionyl chloride which is used as the activating agent in the preparation process generates hydrochloric acid gas and the like, which causes problem in the preparation process. Thus, this method needs to be improved.
In addition, in the above preparation process, a desmethyl impurity and the like, which are difficult to remove, are produced during the reaction. Thus, for a high-purity imatinib base, these impurities need to be removed (see Korean Patent Laid-Open Publication No. 10-2009-0061055).
Furthermore, in Korean Patent Laid-Open Publication No. 10-2009-0128396 which discloses another similar method, dicyclohexylcarbodiimide, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), ethyldimethyl aminopropyl carbodiimide and 2-chloro-1,3-dimethylimidazolium chloride (DMC) were used as coupling agents with the compound of formula (2). For example, a method of preparing imatinib after producing the intermediate of formula (9) using isobutyl chloroformate is represented by the following reaction scheme (3):

The method of reaction scheme (3) produces imatinib in a low yield of 20% or less and is disadvantageous for production of large amounts of imatinib. Thus, it needs to be improved.
Accordingly, during investigation of processes of preparing imatinib of formula (1) and pharmaceutically acceptable salts of imatinib in high purity and high efficiency, the present inventors have found that steps of activating and amidating a carboxylic acid intermediate of the following formula (4) are very important steps that determine the purity of imatinib and have examined various activating agents that selectively activate carboxylic acid from a compound of the following formula (2). As a result, the present inventors have found that the intermediate of the following formula (4) can be prepared in high purity by reacting a compound of the following formula (5) in the presence of a compound of the following formula (6), whereby a desired compound of the following formula (1) can be commercially prepared in large amounts in an economic manner and in high yield and purity, thereby completing the present invention.